3-benzoyl-3-azabicyclo [3. 2. 2] nonanes



United States Patent This application is a continuation-in-part of ourcopending application Ser. No. 276,195, filed Apr. 29, 1963, now US.Patent 3,334,087.

Our invention relates to novel chemical compounds and more particularlyto novel 3-benzoyl-3-azabicyclo- [3.2.2]nonanes and their preparation.The compounds of our invention are amides of 3-azabicyclo[3.2.2]nonaneand can be represented by the formula:

0%: \CH2 i l N-CR CH2 CH2 \CHCH2 wherein R is a substituted orunsubstituted phenyl radical. The substituted or unsubstituted phenylradical R can be represented by the formula:

wherein each of the substituents R is a monovalent radical and at leasttwo of the substituents R are hydrogen. Examples of the monovalentradicals which the substituents R can be include hydrogen, halogen,alkenyl, aryl, amino, cycloalkyl, cycloalkenyl, cyano, carboxy, hydroxy,formyl, nitro, carbamoyl, sulfamoyl, alkoxy, etc.

The halogen atoms which the substituents R can be include fluorine,chlorine, bromine, etc.

R, when alkyl, is typically alkyl of 1 to about 18 carbon atoms and ispreferably lower alkyl, e.g., alkyl of 1 to about 8 carbon atoms.Examples of suitable alkyl substituents include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl,heptyl, octyl, 2-ethylhexyl, decyl, dodecyl, tetradecyl, octadecyl, etc.

When alkenyl, R is typically alkenyl of 1 to about 18 carbon atoms.Included among the useful alkenyl substituents are vinyl, allyl,propenyl, l-butenyl, S-butcnyl, pentenyl, etc., and more complex alkenylsubstituents, such as 2{4-(3-azabicyclo[3.2.2]non-3-ylcarbonyl)phenyl}vinyl, etc.

R, when aryl, is preferably mononuclear carbocyclic aryl of up to about18 carbons such as phenyl; o-tolyl; m-tolyl; p-tolyl;2,3-dimethylphenyl; 2,4-diethylphenyl; 2,5 dipropylphenyl; 2,6dimethylphenyl; 3,4 dibutylphenyl; 3,5-dimethylphenyl; etc.

When amino, R is preferably N-alkylamino, N,N-dialkylamiao, orN-(hydroxyalkyl)amino of up to about 18 carbon atoms. Examples of theamino substituents which R can be include N-methylamino; N-ethylamino;N-propylarnino; N-octylamino; N-isobutylamino; N-pentylamino; N,Ndimethylamino; N,N diethylamino; N-methyl-N-ethylamino;ILIJ-dipentylamino; N,N-diisobutylamino; hydroxymethylamino;Z-hydroxyethylamino; 3-hydroxypropylamino; 4-hydroxybutylamino;3-hydroxybutylamino; etc.

R, when cycloalkyl or eycloalkenyl, typically has 4 to 8 ring carbonatoms such as cyclobutyl, cyclopentyl,

cyclohexyl, cycloheptyl, cyclooctyl, l-cyclobutenyl,

.2-cyclobutenyl, l-cyclopentenyl, Z-cyclopentenyl, 3-cyclopentenyl,l-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, l-cycloheptenyl,2-cycloheptenyl, 3-cycloheptenyl, 4-cycloheptenyl, l-cyclooctenyl,2-cyclooctenyl, 3-cyclooctenyl, 4-cyclooctenyl, etc.

Included among the carbamoyl substituents which R can be areN-alkylcarbarnoyl and N,N-dialkylcarbamoyl groups such asN-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,N,N-dibutylcarbamoyl, N-methyl-N- propylcarbamoyl and more complexsubstituents such as 3-azabicyclo[3.2.2]n0n-3-yl carbamoyl.

Among the sulfamoyl substituents which R can be are N-alkyl sulfamoyland N,N-dialkyl sulfamoyl such as N-ethyl sulfamoyl, N-methyl sulfamoyl,N-butyl sulfamoyl, N-isobutyl sulfamoyl, N-octyl sulfamoyl, N,N-dimethylsulfamoyl, N,N-dipropyl sulfamoyl, N,N diisobutyl sulfamoyl,N-ethyl-N-heptyl sulfamoyl, and more complex substituents such as3-azabicyclo[3.2.2] non-3-yl sulfonyl.

Illustrative of the alkoxy substituents which R can be include methoxy,ethoxy, propoxy, isopropoxy, butoxy, etc. Preferred among the alkoxysubstituents are those having 1 to about 8 carbon atoms.

Among the especially preferred substituents which R can be are hydrogen;chlorine; bromine; hydroxy; nitro; carboxy; sulfo; mcthoxy;3-azabicycl0[3.2.2]non-3-yl carbonyl; S-azabicyclo[3.2.2]non-3-ylsulfonyl; and 2{4- (3-azabicyclo 3 .2.2 non-3-yl carbonyl phenyl}vinyl.

The novel compounds of our invention can be prepared by reacting3-azabicyclo[3.2.2]n0nane with a carbonyl containing compound accordingto the following equation:

The carbonyl containing reactant in the preceding equation can be anacid halide, an acid anhydride, or an ester and the substituent X canthus be halogen, acyloxy, aryloxy or alkoxy. When X is acyloxy, i.e.,when the carbonyl reactant is an acid anhydride, X and R can form a partof the same molecule as in phthalic anhydride. The substituent X, whenaryloxy or alkoxy, can be represented by the formula OR in which R isalkyl or aryl. R when alkyl, is preferably lower alkyl and when aryl ispreferably mononuclear carbocyclic aryl. When the substituent X isacyloxy, the reactant is an anhydride containing the radical o R- -o Aspreviously pointed out, anhydrides of dicarboxylic acids, e.g., phthalicacid, are useful in the process of our invention.

The reaction of the 3-azabicyclo[3.2.2]nonane with the carbonylcontaining compound is preferably carried out by contacting thereactants in a suitable vessel.

The contacting of the reactants is carried out in the liquid phase andthe reaction is therefore generally carried out at a temperature betweenthe melting point and boiling point of the reaction mixture. In manyinstances, the reaction is preferably carried out at room temperaturewhile at other times the reaction is preferably carried out at theboiling point of the reaction mixture, e.g., by heating the reactantsunder reliux.

Stoichiome-tric equivalents of the reactants are preferably employed.Thus, when the carbonyl containing compound has a single reactive siteas in benzoyl chloride, it is preferred to use approximately equimolaramounts of the reactants; but when the carbonyl compound has tworeactive sites, as in terep'hthaloyl chloride, m-chlorosulfonylbenzoylchloride, etc., it is preferred to use about 2 moles of3-azabicyclo[3.2.2]nonane per mole of carbonyl containing compound.However, a stoichiometric excess of either the 3-azabicyclo[3.2.2]nonaneor the carbonyl containing compound can be employed and is oftenpreferred.

When the novel compounds of our invention are prepared by reacting acarboxylic acid halide with 3-azabicyclo[3.2.2]nonane, the reaction ispreferably carried out by contacting the reactants in the presence of abasic compound, e.g., an alkali metal hydroxide, such as sodiumhydroxide, potassium hydroxide, etc.

The reaction is preferably carried out in the presence of an inertsolvent, Suitable inert solvents are those which dissolve each of thereactants but react with neither of them. When a basic compound isemployed, e.g., in the reaction ofa carboxylic acid halide with3-azabicyclo [3.2.2]nonane, the solvent should dissolve the basiccompound as well as both of the reactants.

When the novel compounds of our invention are prepared by reacting anaromatic carboxylic acid or an aromatic carboxylic acid anhydride with3-azabicyclo[3.2.2] nonane, the reaction is preferably carried out bycontacting the reactants in the presence of a catalytic amount of anesterification catalyst. Preferred esterification catalysts are mineralacids, e.g., hydrochloric acid, sulfuric acid, etc., or sulfonic acids,e.g., p-toluenesulfonic acid which are conventionally employed asesterification catalysts. However, such catalysts are not necessary inpreparing the compounds of our invention and can be omitted if desired.If desired, an inert solvent can be employed. In many instances theremoval of water from the reaction zone can be facilitated by the use ofa solvent which forms an azeotrope with Water.

A catalyst can be used when the novel compounds of our invention areprepared by reacting an aromatic carboxylic acid ester with3-azabicyclo[3.2.2]nonane. Examples of useful catalysts are those whichare conventionally employed in ester interchange reactions, i.e., strongacids, e.g., mineral acids such as hydrochloric acid, sulfuric acid,nitric acid, phosphonic acid, etc., or strong bases, e.g., alkali metalhydroxides or alkoxides such as sodium hydroxide, sodium ethoxide, etc.However, a catalyst is not necessary and can be omitted if desired.

The following examples illustrate the novel compounds of our inventionand their preparation.

Example 1.3 (m-bromobenzoyl) -3-azabicyclo [3.2.2]nonane To a one (1)liter three-neck flask equipped with a stirrer, thermometer condenser,addition funnel, and water bath was added 111.4 g. (0.0912 mole)3-azabicyclo [3.2.2]nonane, 3.7 g. (0.0925 mole) sodium hydroxide and200 ml. water. To this stirred mixture was added 20.0 g. (0.0912 mole)m-bromobenzoyl chloride over a sixminute period. The temperature rose to38 C. during the addition. After the addition had been completed, thereaction mixture was stirred for one hour without external heating orcooling. The reaction mixture was cooled to 10 C., and the solid productcollected by filtration to yield 25.1 g, (89.5% of theory) of crude3-(m-bromobenzoyl) 3 azabicyclo[3.2.2]nonane. Recrystallization frommethyl alcohol yielded a product with a melting point of 108112 C.uncorrected.

Analysis.Calcd. for: C, 58.48%; H, 5.84%; N, 4.55%; Br, 25.94%. Found:C, 58.64%; H, 6.24%; N, 4.50%; Br, 25.60%.

Example 2.3-benzoyl-3-azabicyclo [3.2.2] nonane CH2 I II NC a In amanner described in Example 1, 12 g. (0.3 mole) sodium hydroxide, 31.2g. (0.25 mole) 3-azabicyclo [3.2.2]nonane, 150 ml. of water, and 35.1 g.(0.25 mole) benzoyl chloride were reacted to yield 49.6 g. (86.6% oftheory) of crude 3-benzoyl 3 azabicyclo[3.2.2] nonane. Recrystallizationfrom ethanol yielded a product with a melting point of 9394 C.uncorrected.

Analysis.Calcd. for: C, 78.40%; H, 8.23%; N, 6.20%. Found: C, 78.61%; H,8.29%; N, 6.11%.

Example 3 .-3- (Z-hy droxybenzoyl) -3 -azabicyclo [3.2.2] nonaneCHs-CH-CIIz HO To a 500 ml. three-neck flask equipped with a thermometer, stirrer, Vigreux column, and distillation head, was charged32.5 g. (0.26 mole) 3-azabicyclo[3.2.2] nonane, 53.2 g. (0.25 mole)phenyl salicylate and 100 ml. of 1,2,4-trichlorobenzene. The reactionmixture was heated, with stirring, to reflux and the phenol which formedin the head was removed. A total of 1.5 hours reaction time was requiredto remove 16 ml. of phenol, during which time the base temperature rosefrom 187- 191 C. The reaction mixture was filtered hot, then thefiltrate cooled to 20 C. and the solid product collected by filtrationto yield 58 g. (95% of theory) of 3-(2-hydroxybenzyl) 3azabicyclo[3.2.2] nonane. Recrystallization from ethanol yielded aproduct which melted at 203205 C. with partial sublimation at C.uncorrected.

Analysis.-Calcd. for: C, 73.48%; H, 7.75%; N, 5.71%. Found: C, 73.37%;H, 7.83%; N, 560%.

Example 4.3- (3 ,5 -dinitrob enzoyl) -3-azabicyclo [3.2.2]nonane CH2CH2(|JHCH2 N02 To a one (1) liter three-neck flask equipped with stirrerand thermometer was added 31.4 g. (0.25 mole) 3-azabicyclo[3.2.2]nonane, 200 ml. water and 133 ml. of 10% sodiumhydroxide solution. To this stirred mixture was added the solid3,5-dinitrobenzoyl chloride (57.6 g., 0.25 mole) in small portions overa nine-minute period. During this addition the temperature rose from 29C. to 40 C. After the addition had been completed, the reaction mixturewas stirred one hour and then cooled to 20 C. The product was collectedby filtration to yield 43.3 g. (54.3% of theory) of3-(3,5-dinitrobenzoyl) 3- azabicyclo[3.2.2]nonane. Afterrecrystallization from isopropyl alcohol-water, with Darco G60 activatedcarbon for decolorization, the product melted at l58-163 C. uncorrected.

Analy.ri.r.Calcd. for: C, 56.44%; H, 5.33%; N, 13.17%. Found: C, 56.18%;H, 5.44%; N, 13.01%.

Example 5.3-(2-carboxybenzoyl)3-azabicyclo [3.2.2]nonane CHrCH-CH! CH2 NH To a 500 ml. three-neck flask equipped with a stirrer, condenser,thermometer, and addition funnel was added 44.4 g. (0.3 mole) phthalicanhydride and 125 ml. of dry benzene. To this rapidly stirred slurry wasadded a solution of 37.5 g. (0.3 moles) 3-azabicyclo[3.2.2] nonane in 75ml. of dry benzene. After the addition had been completed, the reactionmixture was stirred for one hour and then cooled to C. The solid productwas collected by filtration to yield 72.5 g. (88% of theory) of 3-(2carboxybenzoyl) 3 azabicyclo[3.2.2]nonane, M.P. 181-185 C.

Analysis.Calcd. for: C, 70.34%; H, 6.96%; N, 5.13%. Found: C, 70.35%; H,7.18%; N, 5.25%.

Example 6.-3-{3-(3-azabicyclo [3.2.2] nonan-3-yl. sulfonyl)-benzoyl}-3-azabicyclo [3 .2.2] nonane CHa-CH-CH:

O CH:CHCH H2 II II l I NC- S-N (JHI CH2 H l l O CH: CH; CHz-CH-CH:

In a manner described in Example 1, 62.8 g. (0.5 mole) 3azabicyclo[3.2.2]nonane, 22 g. (0.55 mole) sodium hydroxide, 200 ml.water and 59.8 g. (0.25 mole) mchlorosulfonyl benzoyl chloride werereacted to yield 104 g. (100% of theory) of crude3-{3-(3-azabicyclo[3.2.2] nonan 3 yl sulfonyl)benzoyl} 3azabicyclo[3.2.2] nonane. Recrystallization from isopropyl alcohol-wateryielded a product with a melting point of 146-149 C.

Analysis.Calcd. for: C, 66.35%; H, 7.69%;N, 6.73%. Found: C, 66.09%; H,7.64%; N, 6.76%.

Example 7.p-Bis(3-azabicyclo[3 .2.2] non-3-ylcarbonyl) benzene To a 500ml. three-neck flask equipped with a thermometer, stirrer and solidsaddition funnel was charged 25 g. (0.2 mole) 3-azabicyclo[3.2.2]nonaneand 150 ml. pyridine. To this stirred solution was added 20.3 g. (0.1mole) terephthaloyl chloride over a ten-minute period. After theaddition of the terephthaloyl chloride had been completed, the reactionmixture was stirred for one (1) hour without external heating orcooling. The reaction mixture was cooled to 0 C. and the solid productcollected by filtration to yield 28.2 g. (49.5% of theory) of crudep-bis(3 azabicyclo[3.2.2]non-3-yl carbonyl) benzcne. Recrystallizationfrom dimethylacetamide yielded a product which melted at 290295 C.

Analysis.-Calcd. for: C, 75.80%; H, 8.42% N, 7.37%. Found: C, 75.37%; H,8.56% N, 7.45%.

Example 8.-3- (2,4-dichlorobenzoyl) 3-azabicyclo [3.2.2] nonaneCH2-CHCH2 G1 I O I l N-C Cl CH2 I CHa-JJH-CH:

In a manner described in Example 1, 12.5 g. (0.1 mole) 3-azabicyclo[3.2.2]nonane, 4.2 g. (0.105 mole) sodium hydroxide, 150 ml. waterand 21.0 g. (0.1 mole), 2,4-

dichlorobenzoyl chloride were reacted to yield 27.2 g. (91% of theory)of crude 3-(2,4-dichlorobenzoyl)3-azabicyclo[3.2.2]nonane.Recrystallization from methyl alcohol yielded a product with a meltingpoint of 83-87 C.

Analysis.-Calcd. for: C, 60.44%; H, 5.7%; N, 4.7%; C1, 23.79%. Found: C,60.96%; H, 5.83%; N, 4.50%; Cl, 23.24%.

Example 9.3-anisoyl-3-azabicyclo[3.2.2]nonane o Hz-OH-OH:

1 0 0112 ll 1 T-o-o on.

\ CH: CHzCHCHz In a manner described in Example 1, 3-azabicyclo[3.2.2]nonane (12.5 g., 0.1 mole), sodium hydroxide (4.1 g., 0.102mole), 200 ml. water and anisoyl chloride (17.1 g., 0.1 mole) werereacted to yield 17.2 g. (6.5% of theory) of crude3-anisoyl-3-azabicyclo[3.2.2]nonane. Recrystallization from methylalcohol yielded a product with a melting point of 107-113 C.

Analysis.-Calcd. for: C, 74.14%; H, 8.10%; N, 5.41%- Found: C, 74.10%;H, 8.12%; N, 5.24%.

Example 10.-3-(p-chlorobenzoyl)-3-azabicyclo[3.2.2] nonane Example 11.3,3 [vinylenebis (p-phenylenecarbonyl) bis-3-azabicyclo [3.2.2] nonane CH-CHCH2 CHr-OH-CH 4i id. 3112 Q Q 1 3 CHz-CH-CHz CH2-CH-CH2 In a mannerdescribed in Example 7, 30.5 g. (0.1 mole) of 4,4'-stilbene dicarbonylchloride, 25 g. (0.2 mole) of 3- azabicyclo[3.2.2]nonane, were reactedin 250 ml. of pyridine to yield 36 g. (74.6% of theory).Recrystallization from dimethylformamide yielded a product with amelting point of 25 8263 C. uncorrected. This material has a bluefluorescence under ultraviolet light.

Analysis.-Calcd. for: C, 79.68%; H, 7.88%; N, 5.81%. Found: C, 79.35%;H, 7.85%; N, 5.80%.

Ultraviolet emission peaks at 4-06, 429 and 450 millilTllCI'OI'lS.

Example 12.3-(2-carboxy-3-nitrobenzoyl)3-azabicyclo [3.2.2]nonaneCH2CH-CH2 C0 OH CH: g

N -NO2 I H2 CHa-CH-CH:

In the manner described in Example 5, 48.2 g. (0.25 mole) of3-nitrophthalic anhydride, 31.3 g. (0.25 mole) of3-azabicyclo[3.2.2]nonane and ml. of benzene were reacted to yield 68.3g. (86% of theory) of 3-(2-carboxy- 3-nitrobenzoyl) 3-azabicyclo [3.2.2] nonane. Recrystallization from methyl alcohol yielded a productwhich melted at 230-232" C.

Analysis.-Calcd. for: C, 60.20%; H, 5.95%; N, 8.78%. Found: C, 60.65%;H, 5.65%; N, 8.85%.

The novel compounds of our invention have a variety of uses aschemicals, pharmaceuticals, disinfectants, etc., and as intermediates inthe preparation of various chemicals, pharmaceuticals, disinfectants,etc.

Thus, the compounds of our invention, e.g., 3-benzoyl- 3azabicyclo[3.2.2]nonane; 3 (3,5 dinitrobenzoyl) 3-azabicyclo[3.2.2]nonane; 3 '(3-azabicycl0[3.2.2]non-3-ylsulfonyl)benZo-3-yl-3-azabicycl0[3.2.2]nonane; etc., are useful asbactericides against organisms such as staphylococcus aureus. Thesecompounds can be used as disinfectants, e.g., by mixing them with floorWaxes, soaps, cleaners, etc.

Other compounds of our invention are useful as fungicidal agents and canbe used as fungicidal agents for plants, e.g., by coating the plant witha solution of one of the compounds of our invention in a volatile ornonvolatile solvent, e. g., methyl or ethyl alcohol.

Certain of the compounds of our invention are also useful for preparingdyes or pigments. For example, a dye, useful on polyester and celluloseacetate films, can be prepared by reacting3-(p-aminobenzoyl)-3-azabicyclo [3.2.2]nonane with 4,5-dinitrochrysazinein solution in ethylene glycol. A pigment suitable for incorporation inmelt spun fibers, e.g., polyesters, can be prepared by heating a mixtureof 3-nitro-4-chlorobenzene sulfonamide and3-(p-aminobenzoyl)-3-azabicyclo[3.2.2]n0nane.

The compound 3,3[vinylene bis(p-phenylenecarbonyl)]bis(3-azabicyclo[3.2.2]nonane) when exposed to ultravioletlight, fluoresces blue and is therefore useful as a fluorescentbrightener for textile materials.

The invention has been described in detail with particular reference topreferred embodiments thereof, but it will be understood that variationsand modifications can be effected within the spirit and scope of theinvention as described hereinabove and as defined in the appendedclaims.

We claim:

1. 3-benzoyl-3-azabicyc1o[3.2.2] nonane.

2. 3-(5-dinitrobenzoyl)-3-azabicyclo[3.2.2]nonane.

3. 3 {3 (3 azabicycl0[3.2.2]nonan 3 yl sulfamyl) benzoyl}-3-azabicyclo 3.2.2 nonane.

4. 3,3-[vinylene bis(p phenylene carbamyl)]bis-(3- azabicyc10[3.2.2]nonane).

5. 3-(p-aminobenzoyl)-3-azabicycl0 [3.2.2]nonane References Cited Wagneret al.: Synthetic Organic Chemistry (New York, 1953), pp. 566-569.

ALTON D. ROLLINS, Primary Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,384,636 May 21, 1968 Theodore E. Stanin et a1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 2, lines 34 to 39, the formula should appear as shown below:

Column 6, line 18, "6.5%" should read 66.5% line 40, "5.31" should read5.31% Column 8, line 16, "3-(5- dinitrobenzoyl)" should read3-(3,5-dinitrobenzoyl) Signed and sealed this 28th day of October 1969.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM 'E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents

1. 3-BENZOYL-3-AZABICYCLO(3.2.2)NORANE.